Intestinal Gluconeogenesis Is Downregulated In Paediatric Patients With Coeliac Disease

ObjectiveUntreated coeliac disease (CD) patients have increased levels of blood glutamine and a lower duodenal expression of glutaminase (GLS). Intestinal gluconeogenesis (IGN) is a process through which glutamine is turned into glucose in the small intestine, for which GLS is crucial. Animal studies suggest impaired IGN may have long-term effects on metabolic control and be associated with development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to thoroughly investigate IGN at the gene expression level in children with untreated coeliac disease. DesignQuantitative polymerase chain reaction (qPCR) was used to quantify expression of 11 target genes related to IGN using the delta-delta Ct method with three reference genes (GUSB, IPO8 and YWHAZ) in duodenal biopsies collected from 84 children with untreated coeliac disease and 58 disease controls. ResultsSignificantly lower expression of nine target genes involved in IGN was seen in duodenal biopsies from CD patients compared with controls: FBP1, G6PC, GLS, GPT1, PCK1, PPARGC1A, SLC2A2, SLC5A1, and SLC6A19. No significant differences in expression were seen for G6PC3 and GOT1. ConclusionChildren with untreated coeliac disease have lower expression of genes important for IGN. Further studies are warranted to disentangle whether this is a consequence of intestinal inflammation or due to an impaired metabolic pathway shared with other chronic metabolic diseases. Impaired IGN could be a mechanism behind the increased risk of NAFLD seen in CD patients. SIGNIFICANCE OF THIS STUDYO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIGenome-wide association studies have shown an association between coeliac disease (CD) and glutaminase (GLS). C_LIO_LIIntestinal gluconeogenesis (IGN) is a process with a recently described important function in energy homeostasis and metabolic disease. GLS is critical for IGN by enabling it to use glutamine, its main substrate. C_LIO_LICD patients are at an increased risk of non-alcoholic fatty liver disease (NAFLD) as adults. C_LI What are the new findings?O_LINine genes involved in IGN are downregulated at the gene expression level in the small intestine of children with untreated CD, suggesting impairment of IGN. C_LI How might it impact on clinical practice in the foreseeable future?O_LIImpaired IGN might be a mechanism behind the increased risk of NAFLD seen in CD patients as adults. C_LIO_LIEarly diagnosis and treatment of CD may restore IGN and prevent CD patients from NAFLD later in adulthood. C_LI